Methadone hydrochloride is a long-acting opiate used for treatment of opiate dependence, opiate detoxification and for treatment of chronic, severe pain. Methadone hydrochloride currently approved for use by the FDA is a racemic mixture of levomethadone and dextromethadone, also known as DL-methadone, or (R,S)-methadone.
The active enantiomer of methadone for treatment of opiate dependence, opiate detoxification and for treatment of chronic, severe pain is levomethadone, also known as L-methadone, or R-(−)-methadone. Known methods for preparation of levomethadone may suffer from low overall yield and/or undesirable impurity profiles.
Beckett et al., J Chem Soc, 1957, 858-861, provides a chiral synthesis of levomethadone from D-Alanine in about 7 steps to produce levomethadone in about a 5-6% overall yield from D-alanine.
U.S. Publication US2014/0350302 provides a method for preparing levomethadone comprising racemic synthesis of methadone followed by resolution as a bromocamphor salt. The resolution step introduces undesirable impurities and significantly reduces the overall yield of levomethadone.
An efficient, low cost method for providing levomethadone hydrochloride in good yield, high enantiomeric excess, and with a minimal impurity profile is desirable.
On the other hand, dextromethadone, also known as D-methadone, or (S)-(+)-methadone, is known to be practically devoid of opioid activity, but maintains N-methyl-D-aspartate (NMDA) receptor antagonism. Other NMDA receptor antagonists attenuate neuronal plasticity, reverse opioid analgesic tolerance, and alleviate chronic pain states.
Moryl et al., J Opioid Management, 12:1 January/February 2016, pp. 47-55, disclose a phase I study of D-methadone in patients with chronic pain.
U.S. Publication US 2014/0088155, Manfredi et al., discloses use of D-methadone for the treatment of psychiatric symptoms.
Therefore, efficient, low cost methods are desirable for providing either dextromethadone hydrochloride or levomethadone hydrochloride in good yield, high enantiomeric excess, and with minimal impurity profiles.